Tumor cells escape detection and elimination by the immune system through multiple mechanisms. Immune checkpoint pathways are used in self-tolerance maintenance and activated T cell control, but cancer cells can use the pathways to prevent destruction. The PD-1/human programmed cell death 1 ligand 1 (PD-L1) pathway is one such immune checkpoint. Human PD-1 is found on T cells, and the binding of PD-L1 and human programmed cell death 1 ligand 2 (PD-L2) to PD-1 inhibits T cell proliferation and cytokine production. Tumor cell production of PD-L1 and PD-L2 can therefore allow escape from T cell surveillance.
A fully human IgG4 (S228P) antibody against human PD-1, nivolumab, has been shown to inhibit the binding of PD-1 to PD-L1 and PD-L2, and has been tested in various clinical trials. (Wang et al., Cancer Immunol Res (2014) 2(9): 846). A humanized IgG4 (S228P) antibody against PD-1, pembrolizumab (formerly lambrolizumab), has been shown to inhibit the binding of PD-1 to PD-L1 and PD-L2, and has been tested in various clinical trials. (WO2008156712 and Hamid et al., N Engl J Med (2013) 369:2).
There remains a need to provide alternative antibodies that bind and neutralize human PD-1 interaction with PD-L1 and PD-L2. In particular, there remains a need to provide antibodies that bind human PD-1 with high affinity. Also, there remains a need to provide antibodies that more effectively block the human PD-1 interaction with PD-L1 and PD-L2.